Challenges and Emerging Opportunities for Targeting mTOR in Cancer

Abstract

The mechanistic target of rapamycin (mTOR) plays a key role in normal and malignant cell growth. However, pharmacologic targeting of mTOR in cancer has shown little clinical benefit, in spite of aberrant hyperactivation of mTOR in most solid tumors. Here, we discuss possible reasons for the reduced clinical efficacy of mTOR inhibition and highlight lessons learned from recent combination clinical trials and approved indications of mTOR inhibitors in cancer. We also discuss how the emerging systems level understanding of mTOR signaling in cancer can be exploited for the clinical development of novel multimodal precision targeted therapies and immunotherapies aimed at achieving tumor remission.

Figure 1:. mTOR Signaling Pathway in Cancer.

Schematic depicting major upstream regulatory mechanisms controlling the mTORC1 and mTORC2 complexes, their major functions, and mechanistically distinct classes of pharmacological inhibitors. Numbers indicate the percentage of tumors harboring mutations in indicated pathway members (data retrieved from The Cancer Genomic Atlas (TCGA) PanCancer Atlas Studies via cbioportal.org; mutation frequencies above 1% are shown). Adapted from “mTOR Signaling Pathway”, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates